crossing96/oncoscreening huggingface dataset:
Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer.	Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU-19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose-dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down-regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level.	bladder
Bacillus Calmette-Guérin failure in patients with non-muscle-invasive urothelial carcinoma of the bladder may be due to the urologist's failure to detect urothelial carcinoma of the upper urinary tract and urethra.	BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.	bladder
The use of molecular analyses in voided urine for the assessment of patients with hematuria.	INTRODUCTION: Patients presenting with painless hematuria form a large part of the urological patient population. In many cases, especially in younger patients, the cause of hematuria is harmless. Nonetheless, hematuria could be a symptom of malignant disease and hence most patients will be subject to cystoscopy. In this study, we aimed to develop a prediction model based on methylation markers in combination with clinical variables, in order to stratify patients with high risk for bladder cancer. MATERIAL AND METHODS: Patients (n=169) presenting with painless hematuria were included. 54 patients were diagnosed with bladder cancer. In the remaining 115 patients, the cause of hematuria was non-malignant. Urine samples were collected prior to cystoscopy. Urine DNA was analyzed for methylation of OSR1, SIM2, OTX1, MEIS1 and ONECUT2. Methylation percentages were calculated and were combined with clinical variables into a logistic regression model. RESULTS: Logistic regression analysis based on the five methylation markers, age, gender and type of hematuria resulted in an area under the curve (AUC) of 0.88 and an optimism corrected AUC of 0.84 after internal validation by bootstrapping. Using a cut-off value of 0.307 allowed stratification of patients in a low-risk and high-risk group, resulting in a sensitivity of 82% (44/54) and a specificity of 82% (94/115). Most aggressive tumors were found in patients in the high-risk group. The addition of cytology to the prediction model, improved the AUC from 0.88 to 0.89, with a sensitivity and specificity of 85% (39/46) and 87% (80/92), retrospectively. CONCLUSIONS: This newly developed prediction model could be a helpful tool in risk stratification of patients presenting with painless hematuria. Accurate risk prediction might result in less extensive examination of low risk patients and thereby, reducing patient burden and costs. Further validation in a large prospective patient cohort is necessary to prove the true clinical value of this model.	bladder
An essential role for decorin in bladder cancer invasiveness.	Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49-I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.	bladder
Bubble-driven mixer integrated with a microfluidic bead-based ELISA for rapid bladder cancer biomarker detection.	In this study, fine bubbles were successfully generated and used as a simple, low-cost driving force for mixing fluids in an integrated microfluidic bead-based enzyme-linked immunosorbent assay (ELISA) to rapidly and quantitatively detect apolipoprotein A1 (APOA1), a biomarker highly correlated with bladder cancer. A wooden gas diffuser was embedded underneath a microfluidic chip to refine injected air and generate bubbles of less than 0.3 mm. The rising bubbles caused disturbances and convection in the fluid, increasing the probability of analyte interaction. This setup not only simplifies the micromixer design but also achieves rapid mixing with a small airflow as a force. We used this bubble-driven micromixer in a bead-based ELISA that targeted APOA1. The results indicate that this micromixer reduced the time for each incubation from 60 min in the conventional assay to 8 min with the chip, resulting in a reduction of total ELISA reaction time from 3-4 h to 30-40 min. Furthermore, the concentration detection limit was 9.16 ng/mL, which was lower than the detection cut-off value (11.16 ng/mL) for bladder cancer diagnosis reported in the literature. Therefore, this chip can be used to achieve rapid low-cost bladder cancer detection and may be used in point-of-care cancer monitoring.	bladder
Human papillomaviruses in urological malignancies: a critical assessment.	OBJECTIVES: Infection with human papillomaviruses (HPVs) is intimately associated with anogenital tract malignancies including cervical and vulvar cancer, a subset of oropharyngeal cancers and certain types of skin cancer. A number of urological tumors have likewise been suggested to be associated with high-risk HPV infection; however, many studies are hampered by a limited number of detection methods. The goal of this review article is to define a set of key criteria when implicating a virus in a human cancer and to apply these criteria to HPV infection in urological cancers. MATERIALS AND METHODS: We performed a survey of the literature to corroborate the evidence to support a causal relationship between HPV infection and major urological malignancies. RESULTS: A number of previous reports have implicated HPVs in urological malignancies including penile, prostate, and bladder cancer. Most reports, however, rely only on a limited number of detection methods and frequently use contamination-prone polymerase chain reaction based methods. To firmly establish a link between a viral infection and a human malignancy, it is paramount that an array of techniques is employed and that the virus is ultimately traced by either direct visualization or, in the case of viral genome that has integrated into the host genome, detection of viral genes and gene products as well as functional cellular perturbations. In any case, seroepidemiological studies are likewise crucial to support the evidence. Such evidence for a role of HPV in urological malignancies based on currently available techniques is only present for penile squamous cell carcinomas. CONCLUSIONS: An increasing number of immunocompromised patients as well as novel developments in patient care may change the spectrum of HPV-associated neoplasms. This is examplified by results demonstrating a role of HPVs in rare urothelial carcinomas with squamous differentiation in patients with neurogenic bladder. Hence, it is important to keep HPV infection in mind when confronted with unusual disease manifestations of the urogenital tract.	bladder
Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma.	OBJECTIVES: Evidence suggests a positive effect of metformin on cancer incidence and outcome. To date, the effect of metformin use on prognosis in urothelial carcinoma of the bladder (UCB) remains uninvestigated. We tested the hypothesis that metformin use affects oncologic outcomes of patients treated with radical cystectomy for UCB. METHODS AND MATERIALS: We retrospectively evaluated 1,502 patients treated at 4 institutions with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy. Cox regression models addressed the association of diabetes mellitus (DM) and metformin use with disease recurrence, cancer-specific mortality, and any-cause mortality. RESULTS: A total of 200 patients (13.3%) had DM, 80 patients (5.3%) used metformin. Within a median follow-up of 34 months, 509 patients (33.9%) experienced disease recurrence, 402 patients (26.8%) died of UCB, and 551 patients (36.7%) died from any cause. In univariable Cox regression analyses, DM without metformin use was associated with increased risk of disease recurrence (hazard ratio [HR]: 1.40, 95% confidence interval [CI] 1.05-1.87, P = 0.02), cancer-specific mortality (HR: 1.60, 95% CI 1.17-2.17, P = 0.003), and any-cause mortality (HR: 1.55, 95% CI 1.18-2.03, P = 0.002), whereas metformin use was associated with decreased risk of disease recurrence (HR: 0.61, 95% CI 0.37-0.98, P = 0.04), cancer-specific mortality (HR: 0.56, 95% CI 0.33-0.97, P = 0.04), and any-cause mortality (HR: 0.54, 95% CI 0.33-0.88, P = 0.01). In multivariable Cox regression analyses, DM treated without metformin use remained associated with worse cancer-specific mortality (HR: 1.53, 95% CI 1.12-2.09, P = 0.007) and any-cause mortality (HR: 1.52, 95% CI 1.16-2.00, P = 0.003) but not disease recurrence. CONCLUSIONS: Diabetic patients who do not use metformin appear to be at higher risk of cancer-specific and any-cause mortality than patients without DM. It remains unclear, whether the severity of DM in this group of patients or the use of metformin itself affects outcomes of UCB. The mechanisms behind the effect of DM on patients with UCB and the potential protective effect of metformin need further elucidation.	bladder
Penile metastasis from primary bladder tumour.	OBJECTIVE: We present a case of cutaneous metastasis caused by a bladder tumor. METHODS: 68 year old male, diagnosed with an ISUP high grade urothelial carcinoma, affecting the whole bladder wall, including the perivesicular fat and macroscopic metastasis in the left ilio-obturator chain (T3N2MO), who presents painless induration on the dorsal surface of the glans penis with non-exudative ulcerated areas, evolving over several months. Given the negative serology result, the lesion was biopsied for anatomopathological study. RESULTS: The histopathological study of the lesion corresponded to a cutaneous metastasis from high grade urothelial carcinoma. CONCLUSION: Approximately 370 cases of penile metastasis have been described and the primary tumor is located in the bladder in 30-35% of them. Presentation of these lesions is very heterogeneous and requires anatomopathological study of the lesion for definitive diagnosis.	bladder
Open surgical partial nephrectomy for upper tract urothelial carcinoma.	We aimed to determine the ability of partial nephrectomy to prevent end-stage renal disease and tumor recurrence or progression in patients with upper tract urothelial carcinoma. Retrospectively, eight patients undergoing partial nephrectomy for upper tract urothelial carcinoma were identified and their medical records reviewed. All patients had imperative indications for nephron sparing, and diagnosis of upper tract urothelial carcinoma not adequately amenable to endoscopic management. Although three patients suffered acute tubular necrosis, only one required postoperative hemodialysis. During the follow-up period 25% (2/8) developed end-stage renal disease, including the one patient who had received postoperative hemodialysis. Recurrences occurred in five of seven patients with adequate oncological surveillance. Recurrences were successfully treated endoscopically in 80% (4/5) patients, and one patient had metastases. Of the eight patients, four have died. Death occurred 4 months, 1 year, 1.2 years and 3.5 years after partial nephrectomy. Of these patients, one succumbed to metastatic disease; the exact cause of death is unknown in the other three, but there was no documentation of metastatic cancer. The mean duration of follow up in the remaining four patients, all without evidence of metastatic urothelial cancer, is 71 months (range 22-108 months). In summary, partial nephrectomy for upper tract urothelial carcinoma in patients with imperative indications averts end-stage renal disease in most patients, and appears to be associated with acceptable disease-specific survival. Partial nephrectomy is a sparingly used option in patients with upper tract urothelial carcinoma refractory to endoscopic management who have imperative indications for nephron sparing.	bladder
Hypoxia inducible factor-1alpha and microvessel density as angiogenic factors in bilharzial and non-bilharzial bladder cancer.	BACKGROUND: Hypoxia inducible factor (HIF)-1alpha is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic processes. Microvessel density (MVD), a measure of tumor angiogenesis has been shown to be predictive of progression and poor prognosis in bladder urothelial carcinoma. Most research has relied on measuring HIF-1alpha by immunohistochemistry on tissue sections and studying its prognostic value. However, no study has investigated HIF-1alpha expression by ELISA technique in association with angiogenesis in bilharzial and nonbilharzial bladder carcinoma. The primary objective of this pilot case control study was to measure HIF-1alpha level by ELISA technique in voided urine samples in a trial to find a diagnostic applicability in patients with bilharzial and nonbilharzial bladder carcinoma. Secondary objectives were assessment of MVD in relation to HIF-1alpha positivity as well as correlating them with clinicopathological variables to get insight in their potential prognostic and predictive value in bladder cancer. METHODS: Voided urine specimens were collected from patients with histologically confirmed bladder urothelial carcinoma (Group 1: n = 39), urological patients without urothelial carcinoma (Group 2: n = 15), and healthy volunteers (Group 3: n = 15). All underwent serological assessment of bilharzial antibody, quantitative measurement of HIF-1alpha by ELISA in urothelial cells of voided urine samples and urine cytology. MVD was calculated by immunohistochemical staining of endothelial cells with CD34 on tumor tissue paraffin sections. RESULTS: There was a statistically significant difference between benign and malignant groups regarding HIF-1alpha positivity rate (p < 0.001). Urinary HIF-1alpha best cut-off was determined using receiver operating characteristic curves to discriminate between malignant and nonmalignant groups (21.7 ng/mg protein) at 82.1% sensitivity and 63.3% specificity. The sensitivity of urine cytology was increased on combination with HIF-1alpha from 53.8% to 92.8%. In the malignant group, MVD revealed a high score in 70% and a low score in 30% of cases compared to 0% and 100%, respectively, in the benign group. The difference was highly significant (p < 0.001). There was no significant relationship between HIF-1alpha positivity rate or MVD and stage, as well as histologic grade of the tumor (p > 0.05) denoting no prognostic significance. CONCLUSIONS: HIF-1alpha can be reliably and quantitatively measured in urine of bladder cancer patients, improving the sensitivity and specificity of urine cytology for the diagnosis of bladder cancer. Independent studies, however, will be required on larger cohorts to validate these findings.	bladder
Epidermal growth factor enhances androgen receptor‑mediated bladder cancer progression and invasion via potentiation of AR transactivation.	Androgen receptor (AR) plays a critical role in bladder cancer (BCa) development. Our early studies found AR knock-out mice (with few androgens and deleted AR) failed to develop BCa, yet 50% of castrated mice (with few androgens and existing AR) still developed BCa in an N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) carcinogen-induced BCa mouse model, suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens. The mechanism underlying this and/or which factors potentiate AR function at the castration level of androgen remains unclear. Epidermal growth factor (EGF), a key player in BCa progression, has been demonstrated to be able to potentiate AR transactivation in prostate cancer. In the present study, we found that EGF could increase BCa cell growth, migration and invasion in the presence of AR under the low amount of androgen and EGF was able to potentiate AR transactivation through EGFR by activating PI3K/AKT and MAPK pathway at castration androgen level. The increased suppression effects by EGFR inhibitor of PD168393 on AR function after addition of anti-androgen, Casodex, further suggested AR might play a key role in the effects of EGF on BCa progression and metastasis. Collectively, our results indicate that EGF may be able to potentiate AR transactivation that leads to enhancing BCa progression, which may help us to develop a better therapeutic approach to treat BCa via targeting both EGF and AR signaling.	bladder
Trends in stage-specific incidence rates for urothelial carcinoma of the bladder in the United States: 1988 to 2006.	BACKGROUND: Bladder cancer is notable for a striking heterogeneity of disease-specific risks. Among the approximately 75% of incident cases found to be superficial to the muscularis propria at the time of presentation (non-muscle-invasive bladder cancer), the risk of progression to the lethal phenotype of muscle-invasive disease is strongly associated with stage and grade of disease. Given the suggestion of an increasing percentage of low-risk cases in hospital-based registry data in recent years, the authors hypothesized that population-based data may reveal changes in the stage distribution of early-stage cases. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were used to examine trends for the stage-specific incidence of bladder cancer between 1988 and 2006, adjusted for age, race, and sex, using Joinpoint and nonparametric tests. RESULTS: The adjusted incidence rate of papillary noninvasive (Ta) predominantly low grade (77%) disease was found to increase from 5.52 to 9.09 per 100,000 population (P < .0001), with an average annual percentage change of +3.3. Over the same period, concomitant, albeit smaller, decreases were observed for flat in situ (Tis) and lamina propria-invasive (T1) disease (2.57 to 1.19 and 6.65 to 4.61 per 100,000 population [both P < .0001]; average annual percent change of -5.0 and -1.6, respectively). The trend was most dramatic among patients in the oldest age strata, suggesting a previously unappreciated cohort phenomenon. CONCLUSIONS: The findings of the current study should motivate further epidemiological investigations of differential associations of genetic and environmental factors with different bladder cancer phenotypes as well as further scrutiny of clinical practice guideline recommendations for the growing subgroup of predominantly older patients with lower-risk disease.	bladder